Studies in a variety of solid tumors have shown a correlation between high frequencies of Foxp3+ regulatory T cells (Tregs) and poor patient prognosis. Thus, due to their central role in regulating immune responses, the modulation of Tregs has been the focus of many emerging cancer immunotherapies. While promising, the catastrophic autoimmunity associated with widespread Treg ablation has significantly limited such approaches. Thus, strategies must be developed which specifically target unique aspects of the life-cycle and function of tumor-associated Tregs (taTregs). In order to identify such novel targets, it will be essential to elucidate the fundamental biology behind the development, specificity and function of taTregs in the tumor environment. To better understand endogenous taTreg responses, we analyzed the T Cell Receptor (TCR) repertoire within autochthonous prostate tumors of TRAMP mice. Using this approach, we identified a TCR specificity that was recurrently expressed by a significant proportion of Tregs within the tumor, and was exclusively found in the Treg subset. We then generated transgenic mice expressing this TCR, coined “MJ23," in order to facilitate the study of the antigenic specificity, developmental origins and effects of castration on the anatomical distribution of an endogenous taTreg population. We first determined that MJ23 T cells show poor “induced” Treg development in the periphery, develop into “natural” Tregs in the thymus, and become enriched in the prostate-draining lymph nodes of both tumor-free and tumor-bearing mice, suggesting reactivity to a prostate self antigen. These results support a model in which tumors enrich for thymic-derived Tregs specific for antigens found within the tissue of cancer origin, rather than promoting the differentiation or induction of Foxp3neg CD4+ T cells reactive to tumor neoantigens. Next, to determine the impact of castration (a first line treatment given for locally advanced prostate cancer) on the prostate taTreg population MJ23, one of three treatments was administered: castration, sham castration or castration followed by testosterone restoration. Using this approach, we discovered that castration led to a dramatic increase in thymic cellularity, a selective expansion of thymic MJ23 Treg frequency, and the anatomical redistribution of MJ23 Tregs. Thus, MJ23 Tregs are impacted by the loss of testosterone following castration, leading to systemic redistribution away from the prostate draining lymph nodes. In future studies it will be critical to determine if the effects observed are due to the loss of self antigens or if Tregs themselves are androgen sensitive. Additionally, utilizing this model we will focus on elucidating the in situ function, antigen specificity, and cognate antigen presenting cells within prostate tumors.
Citation Format: Daniel Leventhal, Sven Malchow, Yi Cai, Donald Vander Griend, Peter Savage. Murine prostate tumors recruit endogenous, thymic-derived regulatory T cells which are redistributed following castration. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 452. doi:10.1158/1538-7445.AM2013-452